Malignant pleural mesothelioma (MPM) is a rare aggressive neoplasm that arise primarily from the surface serosal cells of the pleural cavities, generally associated to a poor prognosis. The incidence of MPM is increasing throughout the world, and it is expected to rise in the next 10-20 years because of the increasing exposure to asbestos in past years.
There is no standard of care for the treatment of MPM, and only a minority of patients are eligible for any potentially curative therapy. Complications of cytotoxic chemotherapy strongly influence physician decisions in the treatment of older (65 years of age and older) and/or poor performance status (PS≧2) patients because of the occurrence of frequent and serious co-morbidity events that can complicate therapy (Repetto, J. Support Oncol. 2003, 1(4 Suppl. 2):18-24). Performance status (PS) according to Eastern Cooperative Oncology Group (ECOG, Robert Comis M.D., Group Chair), are scales and criteria used by doctors and researchers to assess how a patient's disease is progressing, to assess how the disease affects the daily living abilities of the patients and determine appropriate treatment and prognosis (Oken, et al. 1982 Am J Clin Oncol 5:649-655). Performance status 2 identifies “ambulatory patients capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours”. Demographic aspects as described above, have to taken into account in the treatment of mesothelioma patients considering that the median age of disease onset is 74 years and that more than 50% of patients have a performance status of 2 or worst at diagnosis (Chapman et al. Thorax 2008, 63(5):435-439).
Over the past 20 years, several approaches have been studied, even if platinum containing regimen demonstrated a greater activity than nonplatinum containing combination, their effects seems to be modest in term of progression free survival (a relatively strong predictive parameter of survival), survival and toxicities (Fennell et al. Nat. Clin. Pract. Oncol. 2008, 5(3): 136-147).
Current progress and clinical data on MPM treatment are reviewed in Ceresoli et al. The Oncologist 2007, 12:850-863. Single modality therapies (surgery, radiotherapy and chemotherapy) have failed to prolong patient survival.
Pemetrexed disodium in combination with cisplatin is the first and only chemotherapy agent that has been granted a marketing approval for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma. However, this chemotherapeutic approach achieved only a modest increase in terms of progression-free (5.7 versus 3.9 months) and overall survival (12.1 versus 9.3 months) in comparison with cisplatin monochemotherapy. Moreover, this chemotherapy combination even if performed in selected patient population (median age 60 years old, Karnofsky performance status at least of 70, that identifies a patient that cares for self and is unable to carry on normal activity or to do active work; or even greater performance status) was unexpectedly toxic and resulted in several treatment related deaths. Toxicity was due to interference with homocysteine metabolism and lead to a change in the protocol, by adding the prophylactic use of vitamin B12 and folate, as a supplementation to therapy. The incidence of serious toxicities with pemetrexed plus cisplatin fully-vitamins supplemented, in the Intent to Treat (ITT) population, was higher compared with the population treated with cisplatin alone (Vogelzang et al. J Clin Oncol 2003, 21 (14): 2636-2644).
At the present time, several biological agents have been evaluated in phase II clinical trials but none resulted to be effective, even if tested in front line and in combination therapy, showing in some circumstances, an unsafe toxicity pattern. Clinical investigations have been focused on epidermal growth factor receptor (EGFR) that is highly expressed in MPM (Destro et al. Lung Cancer 2006; 51:207-215; Edwards et al Lung cancer, 2006; 54:399-407) and on vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) that are important autocrine growth factors in this disease. The use of inhibitors of these receptors has been investigated for the first-line treatment of mesothelioma.
Particularly, in a phase II clinical trial the EGFR inhibitor gefitinib (Iress®), approved for the treatment of advanced non small cell lung cancer, and showing a marked anti-proliferative effect on mesothelioma cells in vitro (Janne et al., Cancer Res 2002, 62:5242-5247), resulted not active as front-line therapy, with a median progression free survival less than three months, although 97% of patients with mesothelioma had EGFR overexpression (Govindan et al. Clin Cancer Res, 2005; 11:2300-2304). In this study gefitinib showed a class specific toxicity profile with the most common grade 3 adverse events (grade 3: severe side-effects) being represented by diarrhoea, skin rash and fatigue.
Likewise, Imatinib (Glivec®), a 2-phenylaminopyrimidine tyrosine kinase inhibitor known to affect both c-Kit and PDGF alpha and beta receptors and approved for the treatment of chronic myeloid leukaemia, didn't show to be effective as front-line single-agent therapy in terms of time to tumour progression (<3 months). Moreover, treatment was interrupted in the 40% of patients due to side effects. The main side effects were oedema (ankles, face, genitals and lungs) sometimes causing exacerbation of pleural or abdominal effusions, nausea and vomiting (Mathy et al. Lung cancer 2005 50:83-86).
The use of angiogenesis inhibitors has been investigated (Ceresoli et al. The Oncologist 2007, 12:850-863). A certain activity was reported with SU5416, a highly selective receptor tyrosine kinase inhibitor that targets the VEGF receptors Flt-1 and KDR/Flk, hampered by an excessive risk for thrombosis.
Valatanib (PTK787) a VEGF and PDGF receptor tyrosine kinases inhibitor showed a median progression free survival of 4 months, when administered to chemotherapy-naïve patients as front-line therapy. Grade 3/4 toxicities (grade 3: severe side-effects, grade 4: life threatening or disabling side-effects) resulted in gastrointestinal bleeding, neutropenia, lymphopenia, nausea/vomiting, increased ALT/AST, hypertension (Jahan et al., J. Clin. Oncol., 2006 ASCO Annual Meeting Proceedings Part I. Vol. 24, No 18S (June supplement), 2006: 7081).
Bevacizumab, a recombinant human anti-VEGF monoclonal antibody that blocks the binding of VEGF to its receptors, was evaluated as front-line treatment combined with chemotherapy in a double-blind, placebo controlled, randomized phase II trial. The combination of bevacizumab plus cisplatin and gemcitabine (BGC) in previously untreated patients did not reach the primary study end point, without any significant improvement in median progression-free survival (6.9 months for BGC vs 6.0 months for chemotherapy alone, p=0.88) or median overall survival (15.6 months for GCB vs 14.7 mo for chemotherapy alone, p=0.91). Moreover a statistically significant higher incidence of different toxicities consisting of alopecia, hypertension, epistaxis, proteinuria, stomatitis, and non neutropenic infection was observed in the bevacizumab arm (Karrison et al., J Clin Oncol. 25 (18S (June 20 Supplement)), 2007: 7526).
All the clinical trials performed so far show that even drugs such as imatinib or gefitinib, already approved for the treatment of certain types of tumors, are not active in mesothelioma. Moreover, drugs resulting to be effective in mesothelioma preclinical models have no activity in humans. These data confirm that the antitumor activity of a drug against certain types of tumor is not predictive of its antitumor activity in another cancer type. Different types of cancer affecting different organs have different aetiology, different underlying spectrum of molecular alterations and a different way of growing. A skilled person is not able to predict whether or not a drug resulting to be effective for the treatment of a tumor would be active against another tumor type.
Currently, there are no standard treatments available for patients progressing following first-line chemotherapy in MPM. This patient population has a very aggressive disease with a median progression-free survival of 1.5 months reported with the use of best supportive care only (Jassem et al., J Clin Oncol. 2008; 26(10):1698-704). The recurrent tumor is almost invariably more resistant to a second-line of treatment than it was at first presentation and treatment (Broxterman et al., Drug Resist Updat. 2003; 6(3):111-27). Moreover patients tolerability to a further line of treatment is generally worse than after first-line chemotherapy (Berthold et al., J Clin Oncol. 005; 23(32):8247-8252).
The aim of a second-line treatment is not only the effectiveness in cancer treatment but also a relative safe and low toxicity profile for the patients.
Several agents have been studied in second-line treatment of mesothelioma, but no improvement of efficacy and toxicity has been observed.
Recently, a randomized, multicentre phase III trial examining pemetrexed plus best supportive care versus best supportive care alone in previously treated mesothelioma patients has been reported. Although a statistically significant longer time to disease progression was demonstrated in the chemotherapy-receiving arm (3.7 months, 95% 2Cl:3.0-4.4) versus the best supportive care arm (1.5 months, 95% Cl:1.4-1.7), no improvement in overall survival was shown (8.4 versus 9.7 months, respectively). The most frequent grade 3/4 toxicities were primarily hematologic and non -hematologic toxicities such as febrile neutropenia and fatigue (Jassem et al., J Clin Oncol 2008; 26(10):1698-704).
In a single-arm, multi-centre Phase II study the combination of bevacizumab plus erlotinib was explored in patients with unresectable mesothelioma who had previously received one prior chemotherapy regimen. Unfortunately, there were no clinical responses in this clinical trial, with a time to tumor progression of 2.7 months. The toxicity profile was characterized by several grade 3 toxicities including skin rash, diarrhoea, thrombosis (Jackman et al., J Thorac Oncol 2007; 2 (8):5602). In another single-arm, multi-centre Phase II study, patients who were either treatment naive or had previously received chemotherapy were treated with the multi-targeted tyrosine kinase inhibitor sorafenib. Among pre-treated patients, the median failure-free survival was 3.6 months. Grade 3/4 toxicity resulted in hand foot reaction and fatigue (Janne P. et al., J Clin Oncol 2007; 25 (18S): Abstract 7707).
Therefore, there is a need of effective drugs, having a favorable toxicity profile, for the treatment of mesothelioma. The present invention addresses this need. We surprisingly found that conjugates comprising a targeting peptide and a cytokine are effective for the treatment of Malignant Pleural Mesothelioma and that such conjugates have a well tolerated toxicity profile.
WO 01/61017 discloses a conjugation product between TNF or IFNγ and a ligand of the CD13 receptor, particularly a peptide containing the NGR motif. Data disclosed in the patent show that TNF conjugates are effective in the treatment of lymphoma and melanoma mouse models. In addition, conjugates of IFNγ and a peptide containing the NGR motif have a potent antitumor effect in lymphoma and fibrosarcoma mouse models (Curnis et al., Cancer Res. 2005; 65(7):2906-2913). Conjugates of various cytokines and tumor targeting moieties have been disclosed (WO 03/092737), and it has been demonstrated (WO 03/093478) that pharmaceutical compositions comprising such conjugates are effective at extremely low dosage that does not induce activation of negative feedback mechanism. WO 2006/067633 discloses peptides containing degradation products of the NGR motif, that are able to target the αvβ3 integrin, and conjugates comprising these peptides and cytokines. None of these document discloses the effectiveness of cytokine conjugates for the treatment of Malignant Pleural Mesothelioma.